Effect of enzalutamide on anticoagulant therapy with edoxaban in patients with prostate cancer.

Abstract

148 Background: Enzalutamide is a potent androgen receptor signal inhibitor used in the treatment of various stages of prostate cancer. However, treatment with enzalutamide is challenging due to its high potential for drug-drug interactions, particularly in the typically older population of prostate cancer patients with often comorbidities treated with multiple drugs. Anticoagulants are such a class of drugs often co-administered with enzalutamide. While low-molecular-weight heparin can be safely combined with enzalutamide, the safety of combining enzalutamide with more patient-friendly direct oral anticoagulants remains uncertain. The objective of this study was to assess whether a drug-drug interaction exists between enzalutamide and edoxaban. Methods: A prospective, multicenter, open-label, two-arm parallel study was performed in men with prostate cancer who are treated with edoxaban, with and without enzalutamide. Plasma concentrations of edoxaban were measured at steady state. Pharmacokinetic (PK) parameters were calculated using non-compartmental analysis. Geometric mean ratios (GMR) of the area under the plasma concentration time curve over one dosing interval (AUC 0-24h ) were calculated. No clinically relevant interaction was defined if 90% of the confidence interval (CI) of the GMR was within the range of 0.8–1.25. Patients kept a patient diary to record medication intake and adverse events. Results: Sixteen patients with prostate cancer using edoxaban (eight patients with enzalutamide and eight patients without enzalutamide) were enrolled. Measured PK parameters are shown in the table. The exposure of edoxaban was similar when combined with enzalutamide, however the 90% CI fell outside of the 0.8-1.25 range (AUC 0–24h GMR 1.03; 90% CI 0.78 – 1.35). No adverse events were reported during the study. Conclusions: The average exposure of edoxaban was similar with and without enzalutamide. However, bioequivalence could not be established due to the broader than anticipated confidence interval. Despite this, the larger variability is not considered to have clinical consequences, supporting the safe co-administration of these drugs in clinical practice. Clinical trial information: NCT05339672 . Pharmacokinetic parameters edoxaban with and without enzalutamide (data are represented as geometric mean (CV%) [confidence interval]). Edoxaban + enzalutamide[90% CI] Edoxaban[90% CI] GMR [90% CI] Edoxaban AUC 0-24h (h*µg/L) 2034.72 (18%)[1711.71 – 2418.68] 1981.94 (47%)[1430.29 – 2746.36] 1.03[0.78 – 1.35] C max (µg/L) 304.30 (28%)[231.79 – 399.48] 254.91 (31%)[198.74 – 326.95] 1.19[0.91 – 1.57] C trough (µg/L) 18.93(37%)[14.12 – 25.37] 21.49 (97%)[11.00 – 41.98] 0.88[0.51 – 1.52] AUC 0-24h , area under the plasma concentration time-curve 0-24 hours; C max , maximum plasma concentration; C trough , trough plasma concentration; GMR, geometric mean ratio; CI, confidence interval; CV, coefficient of variation.